Tutkimus iho- ja sukupuolitautiopin oppiaineessa

Principal Investigator:

Professor Veli-Matti Kähäri, MD, PhD.
Tel: +358-2-3131600; fax:+358-2-3131610; e-mail: veli-matti.kahari (at) utu.fi

Research Group:

Liisa Nissinen, PhD, docent, research scientist
Pilvi Riihilä, MD, PhD, clinical instructor, specialist in dermatology and allergology,
Minna Piipponen, MSc, doctoral candidate
Pegah Rahmati-Nezhad, MD, doctoral candidate
Jaakko Knuutila, MD, doctoral candidate
Kristina Viiklepp, MD, doctoral candidate
Johanna Markola, BSc (eng), project engineer

Description of the research topic:

The incidence of skin cancer, both melanoma and keratinocyte-derived non melanoma skin cancer is increasing in the developed countries due to aging of population and increased recreational exposure to sunlight. In addition, new skin cancer cases are increasing in younger age groups. The growing number of skin cancer patients presents an important challenge to our health care system. Therefore, improved early diagnosis of skin cancer and identification of aggressive premalignant lesions is needed.

In this project our aim is to identify new molecular mechanisms involved in progression of cutaneous squamous cell carcinoma (cSCC), the most common metastatic skin cancer. In the absence of targeted therapies, the prognosis of metastatic cSCC is poor. Furthermore, there are no molecular markers available, which could be used to identify those premalignant precursors, which develop rapidly into invasive carcinomas, or those primary cSCCs which present high risk for metastasis. Our aim is to find and characterize new biomarkers for evaluating the risk of progression and metastasis of cSCC and identify novel therapeutic targets for recurrent and metastatic cSCC. Using microarray and RNA-Seq based global gene expression profiling, we have recently identified a number of novel genes and non-coding RNAs specifically expressed in human cSCCs but in normal keratinocytes. We will characterize the functional role of these genes in progression of cSCC and validate them as biomarkers for growth and metastasis of cSCC.

Another goal of the project is to elucidate the role and regulation of proteinases and MMPs in tissue repair and fibrosis.

Selected Publications:

Riihilä P, Nissinen L, Farshchian M, Kallajoki M, Kivisaari A, Meri S, Grénman R, Peltonen S, Peltonen J, Pihlajaniemi T, Heljasvaara R, Kähäri VM. (2017) Complement components C3 and complement factor B promote growth of cutaneous squamous cell carcinoma. Am J Pathol 187:1186-1197

Farshchian M, Nissinen L, Siljamäki E, Riihilä P, Piipponen M, Kivisaari A, Kallajoki M, Grénman R, Peltonen J, Peltonen S, Quint KD, Bouwes Bavinck JN, Kähäri VM. (2017) Tumor cell specific AIM2 regulates growth and invasion of cutaneous squamous cell carcinoma. Oncotarget 8:45825-45836

Nissinen L, Siljamäki E, Riihilä P, Piipponen M, Farshchian M, Kivisaari A, Kallajoki M, Raiko L, Peltonen J, Peltonen S, Kähäri VM (2017). Expression of claudin-11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ. Exp Dermatol 26:771-777

Farshchian M, Nissinen L, Grénman R, Kähäri VM (2017) Dasatinib promotes apoptosis of cutaneous squamous carcinoma cells by regulating activation of ERK1/2. Exp Dermatol 26:89-92.

Piipponen M, Nissinen L, Farshchian M, Riihilä P, Kivisaari A, Kallajoki M, Peltonen J, Peltonen S, Kähäri VM. (2016) Long Non-coding RNA PICSAR promotes growth of cutaneous squamous cell carcinoma by regulating ERK1/2 activity. J Invest Dermatol 136:1701-1710.

Nissinen L, Farshchian M, Riihilä P, Kähäri VM (2016) New perspectives on role of tumor microenvironment in progression of cutaneous squamous cell carcinoma. Cell Tissue Res 365:691-702.

Rousi E, Koskivuo I, Kaarela O, Kääriäinen M, Kähäri VM. (2016) Clinical and pathological aspects of melanoma among children in Finland. Acta Dermatol Venereol 96:718–720.

Karppinen SM, Honkanen HK, Heljasvaara R, Riihilä P, Autio-Harmainen H, Sormunen R, Harjunen V, Väisänen MR, Väisänen T, Hurskainen T, Tasanen K, Kähäri VM, Pihlajaniemi T. (2016) Collagens XV and XVIII show different expression and localisation in cutaneous squamous cell carcinoma: type XV appears in tumor stroma, while XVIII becomes upregulated in tumor cells and lost from microvessels. Exp Dermatol 25:348-54.

Farshchian M, Nissinen L, Siljamäki E, Riihilä P, Toriseva M, Kivisaari A, Ala-aho R, Kallajoki M, Veräjänkorva E, Honkanen HK, Heljasvaara R, Pihlajaniemi T, Grénman R, Peltonen J, Peltonen S, Kähäri VM (2015) EphB2 promotes progression of cutaneous squamous cell carcinoma. J Invest Dermatol 135:1882-92.

Riihilä P, Nissinen L, Farshchian M, Kivisaari A, Ala-aho R, Kallajoki M, Grénman R, Meri S, Peltonen S, Peltonen J, Kähäri VM. (2015) Complement factor I promotes progression of cutaneous squamous cell carcinoma. J Invest Dermatol 135:579-88.

Riihilä PM, Nissinen LM, Ala-aho R, Kallajoki M, Grénman R, Meri S, Peltonen S, Peltonen J, Kähäri VM (2014) Complement Factor H: a biomarker for progression of cutaneous squamous cell carcinoma. J Invest Dermatol 134:498-506.

Toriseva M, Laato M, Carpén O, Ruohonen ST, Savontaus E, Inada M, Krane SM, Kähäri VM. (2012) MMP-13 regulates growth of wound granulation tissue and modulates gene expression signatures involved in inflammation, proteolysis, and cell viability PLoS One 7(8):e42596.

Toriseva M, Ala-aho R, Peltonen S, Peltonen J, Grénman R, Kähäri VM. (2012) Keratinocyte growth factor induces gene expression signature associated with suppression of malignant phenotype of cutaneous squamous carcinoma cells. PLoS One 7(3):e33041

Farshchian M, Kivisaari A, Ala-aho R, Riihilä P, Kallajoki M, Grénman R, Peltonen J, Pihlajaniemi T, Heljasvaara R, Kähäri VM. (2011) Serpin peptidase inhibitor clade A member 1 (SerpinA1) is a novel biomarker for progression of cutaneous squamous cell carcinoma. Am J Pathol 179:1110–1119

Stokes A, Joutsa J, Ala-aho R, Pitchers M, Pennington CJ, Martin C, Premachandra DJ, Okada Y, Peltonen J, Grénman R, James HA, Edwards DR, Kähäri VM (2010) Expression profiles and clinical correlations of degradome components in the tumor microenvironment of head and neck squamous cell carcinoma. Clin Cancer Res 16:2022-35

Kivisaari AK, Kallajoki M, Ala-aho R, McGrath JA, Bauer JW Königová R, Medvecz M, Beckert W, Grénman R, Kähäri VM. (2010) Matrix metalloproteinase-7 activates heparin-binding epidermal growth factor-like growth factor in cutaneous squamous cell carcinoma. Brit J Dermatol 163:726-735.

Kivisaari AK, Kallajoki M, Mirtti T, McGrath JA, Bauer JW, Weber F, Königová R, Sawamura D, Sato-Matsumura KC, Shimizu H, Csikós M, Sinemus K, Beckert W, Kähäri V.-M. (2008) Transformation specific matrix metalloproteinases (MMP)-7 and MMP-13 are expressed by tumour cells in epidermolysis bullosa-associated squamous cell carcinomas. Brit J Derm 158:778-85.

Junttila MR, Puustinen P, Niemelä M, Ahola R, Arnold H, Böttzauw T, Ala-aho R, Nielsen C, Ivaska J, Taya Y, Lu S-L, Lin S, Chan EKL, Wang X-J, Grénman R, Kast J, Kallunki T, Sears R, Kähäri VM, Westermarck J (2007) CIP2A inhibits PP2A in human malignancies. Cell 130: 51-62.

Junttila MR, Ala-aho R, Jokilehto T, Peltonen J, Kallajoki M, Grénman R, Jaakkola P, Westermarck J, Kähäri V-M. (2007) p38α and p38δ mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells. Oncogene 26:5267-5279.

Toriseva MJ, Ala-aho R, Karvinen J, Baker AH, Marjomäki VS, Heino J, Kähäri V-M.  (2007) Collagenase-3 (MMP-13) enhances remodeling of three-dimensional collagen and promotes survival of human skin fibroblasts. J Invest Dermatol 127:49-59.

Leivonen S-K, Ala-aho R, Koli K, Grénman R, Peltonen J, Kähäri V-M. (2006) Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells. Oncogene 25:2588-2600

Docent Sirkku Peltonen, MD, PhD
sirkku.peltonen (at) utu.fi
Tel +358 2 313 2614

Research group

Co-investigator: Professor Juha Peltonen

Members of the group:
Eija Martikkala PhD,  Roope Kallionpää, MSc, Jussi Leppävirta MD, PhD, Paula Pennanen PhD, Elina Uusitalo PhD, Niina Loponen MD, Heli Ylä-Outinen, MD, PhD, Vivian Visnapuu DDS, PhD, Maria Alanne MD, Kim My Le, BSci, Sini Viitaniemi, BSci
The research group is located at the Department of Dermatology, University of Turku, T-Hospital, Savitehtaankatu 1, 20520 Turku; and at the Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku

Background of the study

Neurofibromatosis type 1 (NF1) is a dominantly inherited neurocutaneous syndrome with incidence of about 1:2000. NF1 is characterized by the appearance of neurofibromas and pigmented spots, café au lait macules in skin. NF1 is the most common monogenic cancer predispositiion syndrome. Although the NF1 gene is known, the function of the corresponding protein tumour suppressor protein neurofibromin is not fully understood.

Research topics of the cell-cell interaction group
1. Epidemiological studies on NF1
3. Mechainsms of tumorigenesis in cutaneous neurofibromas.

The group participates in  ERN GENTURIS http://www.genturis.eu/English/Home.html

Selected publications

Full list of publications

Peltonen S, Kallionpää RA, Rantanen M, Uusitalo E, Lähteenmäki PM, Pöyhönen M, Pitkäniemi J, Peltonen J. Pediatric malignancies in neurofibromatosis type 1: A population-based cohort study. Int J Cancer. (in press) 2019

Ylä-Outinen H, Loponen N, Kallionpää RA, Peltonen S, Peltonen J. Intestinal tumors in neurofibromatosis 1 with special reference to fatal gastrointestinal stromal tumors (GIST). Mol Genet Genomic Med. (in press) 2019

Leppävirta J, Kallionpää RA, Uusitalo E, Vahlberg T, Pöyhönen M, Peltonen J, Peltonen S. Neurofibromatosis type 1 of the child increases birth weight. Am J Med Genet A. 179:1173-1183, 2019.

Leppävirta J, Kallionpää RA, Uusitalo E, Vahlberg T, Pöyhönen M, Peltonen J, Peltonen S. Congenital anomalies in neurofibromatosis 1: a retrospective register-based total population study. Orphanet J Rare Dis. 13(1):5, 2018 doi: 10.1186/s13023-017-0756-4.

Kallionpää RA, Uusitalo E, Leppävirta J, Pöyhönen M, Peltonen S, Peltonen J. Prevalence of neurofibromatosis type 1 in the Finnish population. Genet Med. 2017 Dec 7. doi: 10.1038/gim.2017.215. [Epub ahead of print]

Leppävirta J, Kallionpää RA, Uusitalo E, Vahlberg T, Pöyhönen M, Timonen S, Peltonen J, Peltonen S. The pregnancy in neurofibromatosis 1: A retrospective register-based total population study. Am J Med Genet A. 173(10):2641-2648, 2017. doi: 10.1002/ajmg.a.38372.

Pennanen P, Peltonen S, Kallionpää RA, Peltonen J. The effect of estradiol, testosterone, and human chorionic gonadotropin on the proliferation of Schwann cells with NF1 +/- or NF1 -/- genotype derived from human cutaneous neurofibromasMol Cell Biochem. 2017 Nov 28. doi: 10.1007/s11010-017-3227-2.

Uusitalo E, Kallionpää RA, Kurki S, Rantanen M, Pitkäniemi J, Kronqvist P, Härkönen P, Huovinen R, Carpen O, Pöyhönen M, Peltonen S, Peltonen J. Breast cancer in neurofibromatosis type 1: overrepresentation of unfavourable prognostic factors. Br J Cancer. 116(2):211-217, 2017 doi: 10.1038/bjc.2016.403.

Peltonen S, Kallionpää RA, Peltonen J. Neurofibromatosis type 1 (NF1) gene: Beyond café au lait spots and dermal neurofibromas.Exp Dermatol. 26(7):645-648, 2017 doi: 10.1111/exd.13212.

Uusitalo E, Rantanen M, Kallionpää RA, Pöyhönen M, Leppävirta J, Ylä-Outinen H, Riccardi VM, Pukkala E, Pitkäniemi J, Peltonen S, Peltonen J.Distinctive Cancer Associations in Patients With Neurofibromatosis Type 1. J Clin Oncol. 34(17):1978-86, 2016  

Uusitalo E, Leppävirta J, Koffert A, Suominen S, Vahtera J, Vahlberg T, Pöyhönen M, Peltonen J, Peltonen S. Incidence and Mortality of Neurofibromatosis: A Total Population Study in Finland. J Invest Dermatol. J Invest Dermatol 135:904-6, 2015

Heervä E, Huilaja L, Leinonen P, Peltonen S, Peltonen J. Follow-Up of Six Patients with Neurofibromatosis 1-Related osteoporosis treated with alendronate for 23 months. Calcif Tissue Int. 94:608-12, 2014

Peltonen S, Pöyhönen M, Koillinen H, Valanne L, Peltonen J: Miten tunnistan neurofibromatoosin? Duodecim 130:619–25, 2014

Uusitalo E, Hammais A, Palonen E, Brandt A, Mäkelä VV, Kallionpää R, Jouhilahti EM, Pöyhönen M, Soini J, Peltonen J, Peltonen S. Neurofibromatosis Type 1 gene mutation analysis using sequence capture and high-throughput sequencing. Acta Derm Venereol. 94(6):663-6, 2014